An fMRI Study of Cytokine-Associated Depression and Social Pain

Naomi I. Eisenberger, Ph.D.

Funded in January, 2006: $100000 for 2 years

An fMRI Study of Cytokine-Associated Depression and Social Pain

Recent research has demonstrated a relationship between depression and immune system activity, specifically proinflammatory cytokine activity. Although experimentally-induced immune activation leads to increases in depressed and anxious mood, the neural correlates associated with these changes have remained largely unexplored. Based on relationships between proinflammatory cytokine activity, depression, and heightened physical and social pain sensitivity, this study will investigate the effect of proinflammatory cytokine activation on the neural correlates of socially painful experiences that may contribute to depression. Our previous work has shown that the dorsal anterior cingulate cortex (dACC), typically associated with physical pain distress, also plays a role in the distressing feelings associated with social rejection or social loss ("social pain"). Moreover, recent pilot data has revealed that individuals with elevated levels of baseline proinflammatory cytokines (IL-6) report feeling more socially distressed and show more dACC activity in response to social rejection.

To investigate the causal role that cytokines may play in the heightened social pain sensitivity that can contribute to depression, participants will be randomly assigned to receive either endotoxin (which increases proinflammatory cytokine activity in a safe manner) or placebo. Subsequently, participants will complete a neuroimaging study in which they will be rejected during an online ball-tossing game. We will examine whether individuals exposed to endotoxin report more social distress, endorse more depressive symptoms, and show more dACC activity and more limbic system activity more generally (e.g., amygdala, insula) in response to social rejection. We will also investigate whether, for individuals exposed to endotoxin, greater dACC and general limbic system activity during social rejection mediates the relationship between increased proinflammatory cytokine activity and greater depressive symptoms at the end of the study. The proposed study will be the first to investigate the effect of systemic inflammation on neural reactivity related to social and affective processes that may increase the risk of depression. These findings may have implications for understanding the role of inflammatory mechanisms in depression and have the potential to guide the development of new treatments for this disorder.

Hypothesis:Proinflammatory cytokines are thought to contribute to depression through signaling the central nervous system to promote “sickness behaviors,” such as social withdrawal and increased pain sensitivity, to promote recovery from illness or disease. However, few studies have explicitly tested whether experimental activation of the proinflammatory cytokine network induces depressive symptoms in humans. Moreover, no studies have investigated the specific neurocognitive, affective, or social alterations, induced by inflammation, that make depression more likely.

Our previous work has examined the neural correlates of "social pain," the painful feelings following social rejection or loss, and has shown that the dorsal anterior cingulate cortex (dACC), a neural region associated with the distress of physical pain, also played a role in the distress of social pain. Based on the overlapping neural structures underlying physical and social pain, it is possible that the inflammatory response, aimed, in part, at heightening sensitivity to physical pain, inadvertently recruited systems involved in social pain, heightening sensitivity to social pain as well. We hypothesize that inflammatory mechanisms may induce heightened neural sensitivity to social pain, an experiential state that may contribute to depressive symptoms.

Goals:
The main goal of the present project is to investigate the effect of experimentally induced systemic inflammation on neural reactivity related to social pain processes and depressive symptoms. More specifically, the present project will investigate:

1. Whether experimentally induced systemic inflammation leads to higher levels of "social pain" in response to an experimental episode of social rejection, as well as greater depressive symptoms later on.
2. Whether experimentally induced systemic inflammation leads to greater dACC activity and greater limbic system activity more generally (e.g., amygdala, insula) in response to social rejection.
3. Whether. for individuals exposed to endotoxin, greater dACC and limbic system activity during social rejection mediates or explains the relationship between increased proinflammatory cytokine activity and greater depressive symptoms.

Methods:
To investigate the causal role that cytokines may play in the heightened social pain sensitivity that can contribute to depression, participants will be randomly assigned to receive either endotoxin (which increases proinflammatory cytokine activity in a safe manner) or placebo. Participants will then complete a neuroimaging study in which they will be rejected during an online ball-tossing game. We will examine whether individuals exposed to endotoxin report more social distress, endorse more depressive symptoms, and show more dACC activity and more limbic system activity more generally (e.g., amygdala, insula) in response to social rejection. We will also investigate whether, for individuals exposed to endotoxin, greater dACC and general limbic system activity during social rejection mediates or explains the relationship between increased proinflammatory cytokine activity and greater depressive symptoms at the end of the study.

Amit Etkin is investigating
the use of repetitive transcranial magnetic stimulation in combination with
whole-brain EEG and functional MRI to treat depression and help unravel its
underlying brain circuitry.